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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Identification of Structurally Novel KRASG12C Inhibitors through Covalent DNA-Encoded Library Screening
David Huang, Francesco Manoni, Zhen Sun1
1Department of Therapeutic Discovery, Amgen Asia R&D Center, Amgen Research, 4560 Jinke Road, Pudong, Shanghai 201210, P. R. China.
Abstract:
Covalent inhibition of the KRASG12C oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRASG12C inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen ∼16 million compounds against KRASG12C. We additionally describe the hit identification, validation, and structure-based optimization that culminated in the identification of a series of structurally novel, potent, and selective covalent inhibitors of KRASG12C with good pharmacokinetic profiles and promising in vivo pharmacodynamic effects.
Insights
Researchers developed a novel DNA-encoded library (DEL) to screen millions of compounds for KRAS G12C inhibitors. This approach identified potent covalent inhibitors for non-small cell lung cancer therapy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Covalent inhibition of KRAS G12C is a key strategy for non-small cell lung cancer (NSCLC).
- Traditional screening methods for KRAS G12C inhibitors are limited by library size and diversity.
- DNA-encoded library (DEL) technology offers a powerful platform for screening vast chemical spaces.
Purpose of the Study:
- To design and synthesize a covalent DEL for screening against KRAS G12C.
- To identify novel, potent, and selective covalent KRAS G12C inhibitors.
- To evaluate the pharmacokinetic and pharmacodynamic properties of identified inhibitors.
Main Methods:
- Development of a covalent DNA-encoded library.
- Screening of approximately 16 million compounds against KRAS G12C.
- Hit identification, validation, and structure-based optimization.
- In vitro and in vivo evaluation of inhibitor efficacy.
Main Results:
- Successful design and synthesis of a covalent DEL.
- Identification of a series of structurally novel covalent KRAS G12C inhibitors.
- Demonstration of potent and selective inhibition of KRAS G12C.
- Favorable pharmacokinetic profiles and promising in vivo pharmacodynamic effects.
Conclusions:
- Covalent DEL screening is an effective strategy for discovering novel KRAS G12C inhibitors.
- The identified inhibitors represent promising candidates for NSCLC treatment.
- This approach accelerates the development of targeted cancer therapies.
